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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 788-792

Evaluation of spirometry as a parameter of response to chemotherapy in advanced lung cancer patients: A pilot study


1 Department of Pulmonary Medicine, Government Medical College and Hospital, Chandigarh, India
2 Department of Pulmonary Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India

Date of Submission04-Nov-2017
Date of Acceptance28-May-2018
Date of Web Publication26-Oct-2018

Correspondence Address:
Deepak Aggarwal
Department of Pulmonary Medicine, Block-D, Level.5, Government Medical College and Hospital, Chandigarh - 160 030
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_919_17

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 > Abstract 


Context: Spirometry is an important tool to monitor treatment response in diseases such as chronic obstructive pulmonary disease and asthma. However, there is lack of evidence to support its application to evaluate response to chemotherapy in advanced lung cancer. It might be a useful adjunct to the imaging-based response evaluation which lacks functional assessment of lungs.
Aims: The study was conducted to evaluate the change in spirometry in lung cancer patients after chemotherapy and to find its correlation with change in physical tumor size.
Subjects and Methods: Sixty-two advanced lung cancer patients who were eligible for palliative chemotherapy were enrolled. Baseline tumor size evaluation using Response Evaluation Criteria in Solid Tumor (RECIST)-based scoring system, and spirometry was done. Four cycles of double agent (platinum doublets) chemotherapy were administered, after which treatment response was evaluated. Repeat spirometry was analyzed and correlated with changes in physical tumor size.
Results: Twenty-five patients showed a response (all partial response) to four cycles of chemotherapy. Small cell carcinoma showed a better response rate than non-small cell carcinoma (78% vs. 39%). There was statistically significant improvement in forced expiratory volume in 1 (FEV1) (P = 0.01) and forced vital capacity (P = 0.03) in responders as compared to nonresponders. Change in FEV1 showed a statistically significant correlation with the change in tumor size (RECIST score) (r = –0.34; P = 0.04).
Conclusions: Improvement in spirometry correlates with the tumor response as judged using RECIST criteria after chemotherapy. Further studies with bigger sample size are required to consolidate the results.

Keywords: Lung function, non-small cell lung cancer, response evaluation criteria in solid tumor


How to cite this article:
Aggarwal D, Mohapatra PR, Janmeja AK, Saini V. Evaluation of spirometry as a parameter of response to chemotherapy in advanced lung cancer patients: A pilot study. J Can Res Ther 2020;16:788-92

How to cite this URL:
Aggarwal D, Mohapatra PR, Janmeja AK, Saini V. Evaluation of spirometry as a parameter of response to chemotherapy in advanced lung cancer patients: A pilot study. J Can Res Ther [serial online] 2020 [cited 2020 Sep 29];16:788-92. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/788/244240




 > Introduction Top


Lung cancer is the most common cancer worldwide with an estimated 1.8 million new cases occurring in 2012 which accounted for about 13% of the total cancer diagnosis.[1] It is also the most common carcinoma in India where approximately 63,000 new lung cancer cases are reported each year.[2] About 80% of these patients present in advanced stage (Stage III and IV) of the disease, thus excluding them from potentially curative modes of treatment.[3] However, with the advent of newer chemotherapies regimens and targeted therapies, the survival of these patients is improving.

Computed tomography (CT)-based measurement of physical tumor burden using Response Evaluation Criteria in Solid Tumors (RECISTs) criteria is the standard tool for evaluation of treatment response in lung cancer.[4] However, these criteria do not incorporate lung function evaluation into the overall assessment of treatment response. Improvement in functional status is an important assessment criteria which seems more relevant than the decrease in physical tumor size for the patients with advanced disease and being treated with palliative intent. It seems logical that with decrease in the size of tumor that is invading the airways/lung, the lung function should improve. However, there is lack of evidence to prove whether the reduction in tumor size after chemotherapy is associated with expected improvement in lung functions. Data from previous studies have shown mixed results with a few showing significant improvement[5] while other yielding an equivocal response[6] in lung function parameters.

Spirometry is a simple and cost-effective investigation that is free from radiation exposure. This along with diffusion capacity to carbon monoxide (DLCO) is routinely used to predict postoperative outcome in early-stage lung cancer as well as to evaluate improvement after stereotactic body radiotherapy in medically inoperable patients.[7],[8] However, their role as treatment response parameter in advanced lung cancer patients has not been studied yet. Hence, the present study was planned to evaluate spirometry changes after palliative chemotherapy and to study its correlation with physical tumor size (measured using RECIST criteria) in advanced lung cancer patients.


 > Subjects and Methods Top


This was a single-center prospective observational study conducted in Government Medical College and Hospital (GMCH), Chandigarh over a period of 3 years (January 2014–December 2016). Patients of advanced lung cancer (Stage III B and IV) having a good performance status (Eastern Cooperative Oncology Group performance status 0–1)[9] and eligible for palliative chemotherapy were enrolled. Subjects with completely nonmeasurable disease, poor performance status, unfit for chemotherapy, and those who were planned for concurrent chemoradiation were excluded from the study. At 5% level of significance and 80% power, a sample size of 50 patients was required to achieve an expected correlation of 0.40 between spirometry and RECIST score. After adjusting for 20% lost to follow-up, a sample size of 60 patients was planned for the study. Informed and written consent was taken from each patient. The study was approved by Institutional Ethics Committee of GMCH.

Tumor burden

Tumor size (in centimeter) was measured objectively using a contrast-enhanced CT (CECT) of the thorax (with 5 mm slice thickness) using standard revised RECIST criteria (version 1.1).[4] Target and nontarget lesions were selected on CT at baseline. The longest diameter (for organs) and short axis diameter (for lymph nodes) of the target lesions was added to get “baseline sum diameter.” Simultaneously patients also underwent baseline spirometry test on RMS Helios 401 PC-based Spirometer. Flow rates, i.e., forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured as percentage predicted and ratio of FEV1 and FVC was derived as per recent the American Thoracic Society guidelines.[10]

Treatment

All patients were given four cycles of induction chemotherapy using platinum-based double agents. None of the patients who were tested for epithelial growth factor receptor mutation and anaplastic lymphoma kinase rearrangement yielded positive results. The drug combinations used included either gemcitabine, pemetrexed, or paclitaxel combined with Carboplatin/Cisplatin depending on the tumor histopathology.[11] Small cell carcinoma was treated with combination therapy using cisplatin and etoposide. Treatment of comorbidities, notably, chronic obstructive pulmonary disease (COPD) was continued as per the standard guidelines.

After completion of four cycles, a repeat CECT thorax and spirometry were performed to get the posttreatment values. Tumor response, measured as a change in tumor size on CT thorax, was categorized as complete response, partial response, stable disease, or progressive disease as per the RECIST criteria. For the purpose of analysis, patients were said to be “responders” if they had a complete or partial response after chemotherapy and were described as “nonresponders” if they had stable or progressive disease.[5] Change in spirometry values was compared and correlated with change in tumor size using appropriate statistical tests.

Statistical analysis

Data were statistically described in terms of mean ± standard deviation, median with range or frequencies, wherever appropriate. Comparison of continuous variables between two groups was done using Student's t-test for independent variables/Mann–Whitney U-test. Correlation between RECIST score and lung function parameters (FEV1 and FVC) was carried out using Pearson correlation. For all analysis, P < 0.05 was considered statistically significant. All statistical calculations were done using computer program SPSS (IBM SPSS Statistics 21.0; Armonk, NY, USA).


 > Results Top


Out of 62 patients, 50 completed four cycles of chemotherapy and were included for final analysis. Out of remaining, four were lost to follow-up, seven patients were given modified palliative treatment due to drug intolerance, and one patient died before completing four cycles of chemotherapy. The baseline characteristics are shown in [Table 1]. Majority of patients were current or reformed smoker males with median duration of symptoms of 2 months.
Table 1: Demographic and clinical characteristics of lung cancer patients

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Squamous cell carcinoma was the most common histopathological type (n = 24) followed by small cell carcinoma (n = 14) and adenocarcinoma (n = 12). Twenty-five patients (50%) had a partial response to chemotherapy. Tumor response was seen more frequently in small cell lung cancer (SCLC) patients as compared to non-SCLC (NSCLC) (78% in SCLC vs. 39% in NSCLC P = 0.02) [Table 2]. There was no difference in age, gender, duration of symptoms, presence of COPD, and number of pack-years between responders and nonresponders (P = 0.05).
Table 2: Treatment outcomes between 2 histopathological types of lung cancer

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Change in spirometry

There was a statistically significant improvement in the spirometry values (FEV1 and FVC) in patients who responded to chemotherapy as compared to nonresponders (P = 0.01 and 0.03, respectively) [Table 3]. Change in RECIST score had statistically significant negative correlation with change in FEV1(r = −0.34; P = 0.04) [Figure 1]a whereas it had no association with change in FVC (r = −0.22, P = 0.20) [Figure 1]b. On subgroup analysis, small cell carcinoma showed significant improvement in lung functions irrespective of the treatment outcome [Table 4].
Table 3: Comparison of spirometry changes between dresponders and nonresponders

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Figure 1: Scatter plot showing correlation between changes in tumor size and (a) change in forced expiratory volume in 1 (b) change in forced vital capacity. Note: Negative values on x and y axis show decrease in the respective variable and vice versa

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Table 4: Change in spirometry in different histopathological types of lung cancer after chemotherapy

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 > Discussion Top


The present study evaluated the application of spirometry as a tool to monitor response to chemotherapy in advanced lung cancer. The results showed a statistically significant improvement in spirometry in patients who responded to chemotherapy as compared to nonresponders. FEV1 also showed a statistically significant negative correlation with change in tumor size.

Half of the patients (n = 25) in the present study achieved partial response after four cycles of double agent chemotherapy. The decrease in tumor size was accompanied by statistically significant improvement in FEV1 and FVC in these patients [Table 3]. It was also seen that the number of COPD patients as well as pack-years of smoking was not significantly different between responders and nonresponders groups (P = 0.3 and 0.53, respectively). Hence, the effect of COPD as a confounding factor affecting change in lung function could be reasonably excluded from the study. With few differences in the study designs, data from few previous studies also support the association between the change in lung functions and change in tumor size.[5],[12] On the other hand, certain studies did not yield a significant change in either of the spirometric values after chemotherapy.[6],[7],[8] This disparity in the results may be due to the difference in the inclusion criteria for subjects, the difference in the treatment regimens followed as well as variation in the time between treatment and analysis in these studies. Interestingly, the significant and expected improvement in spirometry found in responders in our study was not retained in patients with NSCLC on subgroup analysis [Table 4]. However, less number of patients in individual histological types of cancer might have affected the results in the study. Bigger sample size studies targeting individual histological types might confirm the association between the 2 parameters.

In the present study, we tried to find out the correlation between change in spirometric values and tumor size (RECIST score) after controlling for COPD and pack-years of smoking. Even though both FEV1 and FVC showed statistically significant improvement in responders, only FEV1 showed mild-to-moderate degree of negative association with tumor size change (r = −0.34; P = 0.04) on linear correlation. Lack of strong correlation between the 2 could be due to the fact that, apart from COPD, lung functions are known to be affected by certain comorbidities such as diabetes and hypertension as well as by dietary factors/deficiencies, etc., that might have affected its association with tumor size.[13] Moreover, cachexia and muscle weakness occurring due to detrimental effects of advanced cancer and/or chemotherapy also might have diluted the expected spirometric improvement after chemotherapy. Evaluating the association after adjusting these possible confounders might have given a better picture about their association.

Theoretically, lung cancer can affect pulmonary functions in any 1 of the 4 ways; obstructive (due to intraluminal growth or external compression of the airways without concomitant atelectasis), restrictive (in atelectasis, pleural effusion, etc.,) mixed, and no/minimal defect (in coin lesions).[5] Hence, improvement in spirometry after chemotherapy also depends on the anatomical location and extent of involvement of the tumor with maximum improvement expected in lesion occluding the airway and minimal in solitary pulmonary lesion. However, practically seen, it is often difficult to categorize the patients completely into these anatomical types. Further studies, classifying the patients and then evaluating the change in lung functions with chemotherapy might prove the hypothesis.

In the present study, 28% patients (n = 14) were diagnosed to have small cell histopathology. On subgroup analysis, small cell carcinoma showed significant improvement in both FEV1 and FVC irrespective of the response [Table 4]. This is probably due to chemosensitive nature of these tumors that resulted in a significant response rate of 78% in the present study. With predominant central airway involvement, decrease in tumor size with chemotherapy might have led to improvement in flow rates in small cell carcinoma. There is a scarcity of studies on lung functions changes in small cell carcinoma; hence, the results need validation in studies enrolling lung cancer patients with the specific histology.

The present study gave an insight into the application of a simple and cost-effective test, spirometry, in evaluating response to chemotherapy in advanced lung cancer. We could not find another study with a similar aim and design published from an Indian setting. However, a small sample size of 50 patients might have affected the results, especially on subgroup analysis. Nevertheless, encouraging results achieved in this pilot study has given a new dimension to the treatment response monitoring in lung cancer that should be explored further. We did not include DLCO in the final analysis as only 9 patients could perform the test. This may be due to the fact that maneuver to perform DLCO is more difficult for lung cancer patients as compared to routine spirometry. Moreover, DLCO has been previously evaluated to assess the toxic effects of neoadjuvant chemotherapy in lung cancer and not primarily as a monitoring tool.[8],[14],[15]


 > Conclusion Top


The present study showed that decrease in tumor burden after chemotherapy is associated with improvement in spirometry, particularly FEV1. The results suggest the use of spirometry for monitoring of functional assessment of lung cancer patients on chemotherapy. However, in view of multiple factors affecting the spirometry, studies with higher sample size and adjustment for confounding factors are required that might help to validate its place in the monitoring of lung cancer.

Financial support and sponsorship

The study was financially supported by the Department of Science and Technology, Chandigarh, India.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Pinson P, Klastersky J. The value of lung function measurements for the assessment of chemotherapy in lung cancer patients. Lung Cancer 1998;19:179-84.  Back to cited text no. 5
    
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Dimopoulou I, Efstathiou E, Samakovli A, Dafni U, Moulopoulos LA, Papadimitriou C,et al. A prospective study on lung toxicity in patients treated with gemcitabine and carboplatin: Clinical, radiological and functional assessment. Ann Oncol 2004;15:1250-5.  Back to cited text no. 8
    
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET,et al. Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol 1982;5:649-55.  Back to cited text no. 9
    
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Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A,et al. Standardisation of spirometry. Eur Respir J 2005;26:319-38.  Back to cited text no. 10
    
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Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR,et al. Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017;15:504-35.  Back to cited text no. 11
    
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Leo F, Solli P, Spaggiari L, Veronesi G, de Braud F, Leon ME,et al. Respiratory function changes after chemotherapy: An additional risk for postoperative respiratory complications? Ann Thorac Surg 2004;77:260-5.  Back to cited text no. 12
    
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Ostrowski S, Barud W. Factors influencing lung function: Are the predicted values for spirometry reliable enough? J Physiol Pharmacol 2006;57 Suppl 4:263-71.  Back to cited text no. 13
    
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Videtic GM, Stitt LW, Ash RB, Truong PT, Dar AR, Yu EW,et al. Impaired diffusion capacity predicts for decreased treatment tolerance and survival in limited stage small cell lung cancer patients treated with concurrent chemoradiation. Lung Cancer 2004;43:159-66.  Back to cited text no. 14
    
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Takeda S, Funakoshi Y, Kadota Y, Koma M, Maeda H, Kawamura S,et al. Fall in diffusing capacity associated with induction therapy for lung cancer: A predictor of postoperative complication? Ann Thorac Surg 2006;82:232-6.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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